Production of i-aminoindan derivatives



PRODUCTION OF l-AMINOINDAN DERIVATIVES Helmer Richter, Berlin-Grunewald,and Martin Schenck, Berlin-Frohnau, Germany, assignors t Firma ScheringA. G., Berlin, Germany No Drawing. Application April 3, 1957 Serial No.650,313

Claims priority, application Germany April 13, 1956 20 Claims. (Cl.260-575) show various valuable physiological properties in many However,no coronary blood vessel dilating directions. action has been observedfor the known compounds.

It is accordingly a primary object of the present invention to providenew l-aminoindan compounds, which compounds have a high activity ascoronary blood vessel dilators.

It is'another object of the present invention to provide a method ofproducing such l-aminoindan derivatives.

Other objects and advantages of the present invention will be apparentfrom a further reading of the specification and of the appended claims.

With the above objects in view, the present invention mainly consists innew l-aminoindan derivatives which are unsubstituted in the S-memberring and which have an alkoxy group in the -position of the benzenering, the alkoxy group containing more than 3 carbon atoms. Preferablythe alkoxy group should contain between 4 and 8 carbon atoms, and mostpreferably between 4 and 6 carbon atoms. Thus, the new compounds of thepresent invention have the following structural formula:

in which R is an alkyl group of more than 3 carbon atoms and preferablyof 4-8 carbon atoms.

The new alkoxy-l-aminoindan compounds of the pres ent invention can beproduced by hydrogenating the oxime or the oxiine ether of thecorresponding alkoXy-l-indanone in an organic solvent, preferably analcohol, in the presence of a hydrogenation catalyst such as Raneynickel or a noble metal catalyst such as palladium black, with theaddition of a mineral acid, preferably at moderately increasedtemperatures and normal pressure.

It has been found that the hydrogenation of the oxime ethers inaccordance with the present invention does not yield the l-hydroxylamino compound as would be expected, but rather the l-amino compounds ofthe present invention. Therefore, it is possible in accordance with thepresent invention to utilize the oxime ether instead of the free oximeas the starting substance. This can be of advantage since it has beenshown that the usual production of the oxime from the correspondingalkoxy-1-indanones in many cases results in difficulties while it runssmoothly when oxy-l-indanones are utilized as the starting material.volved in the subsequent alkylation of the hydroxyl group of oximes ofoxy-l-indanone according to the known i ed States Patent 0 F On theother hand, there are no difl'iculties in- 2,832,804 Patented Apr. 29,1958 2 methods, whereby, of course, the oxime hydroxyl group isalkylated at the same time.

A preferable method for the production of the starting material which isutilized in the method of the present invention is illustrated by thefollowing equations, the scope of the invention, however, not beinglimited thereto. In the equation R stands for an alkyl radical of morethan 3 carbon atoms.

Haggai I l I l The method of the present invention can then proceedaccording to the folowing equation:

NOX NH:

in which X stands for a hydrogen atom or the alkyl group R.

It should be noted that the alkoxy-l-aminoindan compounds in which thealkoxy group contains less-than 4 carbon atoms have substantially noaction on the coronary vessels. It is only the higher alkoxy derivativesof the present invention which have a substantial coronary blood vesseldilating action. This is illustrated by the following table.

The trade preparation Khellin which is5,8-dimethoxy-2-methyl-(furano-2',3'27,6-chromone) was utilized as thecomparison substance.

Besides a superior activity with simultaneously lowered toxicity, thecompounds of the present invention possess the advantage over the knownproduct Khellin of being water-soluble in the form of their acidaddition salts.

Toxicity, Coronary vessel dilating action in LD-50, percent on theLangendorfi heart Tested Compound intravenalter the administrationofous, 111 mg. per kg. of rat 107 20 507 152 no action no action 28. 107do do 15. fi-isoproxy- 137 30. 5-butyl0xy- 137 25 65. fi-hexyloxy- 53200 230. l-aminotudan-hydrochloride. E-methoxy- 86.7 no action. noactlomno action. Z-amlnoindan-hydrochloride. Khellin 34.4 d0--- 18 32.

The S-heptyloxy-l-aminoidan and S-oxtyloxy-l-aminoindan compounds alsohave superior therapeutic activity.

As opposed to the above, the known preparation oxyethyl-theophylline bythe same testing method gives a value of 4% only after theadministration of 200 of the substance. The LD-SO of this substance is486.

The following examples are given to illustrate the method of the presentinvention and the production of compounds of the present invention, thescope of the invention not, however, being limited to the specificdetails of the examples.

Example 1 6.5 g. of -oxyindanone-(1) (melting point=182 C.), obtainedfrom m-oxyhydrocinnamic acid (melting point: 108-110 C.) which lendsitself to cyclizatiou, for example by means of hydrofluoric acid(Organic Reactions, vol. II, 1944, page 125, J. Wiley 8: Sons), aredissolved in 25 cc. of pyridine and mixed with a solution of 3.3 g. ofhydroxylamine-hydrochloride in 10 cc. of 80% ethyl alcohol. Afterstanding for 48 hours at room temperature, the reaction mixture ispoured into water. The separated S-oxyindanone-oxime-(l) is sucked-offby filtration and dried. The melting point is 208-210 C. withdecomposition and the yield is 5 g. The product can, Without furtherpurification, be subjected to esterification.

4.1 g. of 5-oxyindanone-oxime-(l) is mixed with 50 cc. of isopropylalcohol, 3.4 g. of powdered potassium hydroxide and 7.1 g. of isopropylbromide, and the mixture is heated to refluxing for 8 hours. The mixtureis poured into water and. the diether is taken up. with chloroform. Thechloroform extract is washed with water and then concentrated undervacuum. There is thereby immediately obtained a pure N-isopropoxy etherof 5-isopropoxy-indanone-oxime-(1) which melts at 224 C. withdecomposition. Non-converted S-oxyindanoneoxime-( 1) can be re-obtainedfrom the aqueous phase by acidification.

1.8 g. of the diether is dissolved in cc. of methanol and the solutionis mixed with 0.2-0.3 cc. of concentrated hydrochloric acid. With theintroduction of palladium black as catalyst the mixture is hydrogenatedunder normal pressure at C. After about 15 hours, the amount of hydrogentaken up corresponds to 100% of the theoretical. The catalyst is thenseparated and the filtrate concentrated under vacuum under theprotection of a nitrogen atmosphere. There is thus obtained 1.3 g. ofcrude S-isopropoxy-1-aminoindan-hydrochloride. The substance can bere-crystallized from methanol-ether. 1.1 g. of the hydrochloride havinga melting point of 172173 C. is obtained.

Example 2 5.5 g. of S-butoxy-indanone-(l) (a wax-like substance)obtained from m-butoxy-hydrocinnamic acid (melting point=80-84 C.),which is for example cyclized by means of polyphosphoric acid, aredissolved in 15 cc. of pyridine and mixed with a solution of 2.2 g. ofhydroxylamine hydrochloride in 7 cc. of 80% alcohol. The reactionmixture is allowed to stand for 48 hours at room temperature and is thenpoured into water. The separated S-butoxy-indauone-oxime-(l) is suckedoff under vacuum and dried. The melting point is 155 157 C. The yield is6 g. The product can without further purification be subjected tohydrogenation.

6.9 g. of S-butoxy-indanone-oxirne are dissolved in 70 cc. of methanoland mixed with 1 cc. of concentrated hydrochloric acid. The product issubjected to hydrogenation utilizing palladium black as catalyst undernormal pressure and at a temperature of 40 C. After 25 hours the amountof hydrogen taken up corresponds to 95% of the theoretical. The catalystis separated and the solution is concentrated under vacuum under theprotection of a nitrogen atmosphere. The residue is re-precipitated frommethanol-ether. There is thus obtained 4 g. ofS-butoxy-l-aminoindane-hydrochloride having a melting point of 152 155C.

Example 3 23.2 g. of S-hexyloxyindanone-(l) having a melting point ofabout 80 C. (wax-like bodies) obtained from m-hexyloxyhydrocinnamic acid(melting point=53 -S5 C.) which can be cyclized for example by means ofpolyphosphoric acid, are dissolved in cc. of pyridine and mixed with asolution of 8.4 g. of hydroxylamine hydrochloride in 25 cc. of ethylalcohol. After standing for 48 hours at room temperature the reactionmixture is poured into water. The separated S-hexyloxyindanoneoxime-(l)is sucked off under vacuum and dried. The melting point is 98-100 C. andthe yield is 20.6 g. The product can, without further purification, besubjected to hydrogenation.

2.5 g. of S-hexyloxyindanone-oxime-(l) are dissolved in 30 cc. ofmethanol, mixed with 0.3-0.4 cc. of concentrated hydrochloric acid andhydrogenated under normal conditions utilizing palladium black ascatalyst. After 25 hours the amount of hydrogen taken up corresponds to97.2% of the theoretical. The catalyst is separated and the solutionconcentrated under vacuum to dryness. The thus obtained crudeS-hexyloxy-l-aminoindan hydrochloride melts at 156159 C. The yieldamounts to 2.3 g. The hydrochloride can be re-crystallized from water.There is thus obtained 2 g. of a product which melts at 164l65 0, thisproduct being S-hexyloxy-laminoindan.

The hydrogenation can also be carried out utilizing Raney nickel ascatalyst, as follows:

12.3 g. of S-hexyloxy-indanone-oxime-(1) is dissolved in 80 cc. ofmethanol and the solution is poured into a hydrogen bomb. It is ofadvantage to add some liquid ammonia. The hydrogenation is then carriedout utilizing Raney nickel as catalyst at a temperature of 70 C. andunder atmospheres of pressure. After 90 minutes the take-up of hydrogenis completed. The catalyst is separated, the solution evaporated todryness under vacuum and the residue taken up in ether. Thehydrochloride is precipitated by ethereal hydrochloric acid and thehydrochloride is reprecipitated from emthanol-ether. The yield amountsto 11.2 g. of S-hexyloxy-l-aminoindan hydrochloride which melts at -l64C.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this inventionand, therefore, such adaptations should and are intended to becomprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be secured by Letters Patent is:

1. As a new composition of matter, a l-aminoindan compound having thefollowing structural formula:

2. As a new composition of matter, a l-aminoindan compound having thefollowing structural formula:

in which R isian alkyl group of 4-8. carbon atoms.

3. As a new composition of matter, a l-aminoindan compound having thefollowing structural formula:

in which R is an alkyl group of 4-6 carbon atoms,

4. As a new composition of matter, non-toxic acid addition salts of thecompound of claim 1.

5. As a new composition of matter, the hydrochloride of the compound ofclaim 1.

6. As a new composition of matter, S-butoxy-l-aminoindan.

7. As a new composition of matter, S-butoxy-l-aminoindan hydrochloride.

8. As a new composition of matter, S-hexyloxy-laminoindan.

9. As a new composition of matter, S-hexyloxy-laminoindan hydrochloride.

10. A method of producing a -alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oXime ether of a 5-alkoxy-1-indanone dissolved in anorganic solvent therefor to hydrogenation in the presence of ahydrogenation catalyst so as to form a corresponding 5-alkoxy-l-amino-indan; and recovering the thus formedS-alkoxy-l-amino-indan.

11. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a S-alkoxy-l-indanone, the alkoxy group ofwhich contains more than 3 carbon atoms, dissolved in an organic solventtherefor to hydrogenation in the presence of a hydrogenation catalyst soas to form the corresponding S-alkoxy-l-aminoindan; and recovering thethus formed S-alkoxy-l-aminoindan.

12. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a 5-alkoxy-1-indanone, the alkoxy group ofwhich contains between 4-8 carbon atoms, dissolved in an organic solventtherefor to hydrogenation in the presence of a hydrogenation catalyst soas to form the corresponding S-alkoxy-l-aminoindan; and recovering thethus formed S-aIkoXy-I-aminoindan.

13. A method of producing a S-aIkoXy-I-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a 5-alkoxy-1-indanone dissolved in analcohol to hydrogenation in the presence of a hydrogenation catalyst soas to form the corresponding S-alkoxy-l-aminoindan; and recovering thethus formed S-alkoxy-l-aminoindan.

14. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a S-alkoxy-l-indanone dissolved in methylalcohol to hydrogenation in the presence of a hydrogenation catalyst soas to form the corresponding S-alkoxy-laminoindan; and recovering thethus formed 5-alkoxy-laminoindan.

15. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a 5-alkoxy-l-indanone dissolved in anorganic solvent therefor to hydrogenation in the presence of ahydrogenation catalyst selected from the group consisting of Raneynickel and noble metals and in the presence of a mineral acid so as toform the corresponding 5-alkoxy-1-aminoindan; and recovering the thusformed 5-alkoxy-1-aminoindan.

16. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a S-alkoxy-l-indanone dissolved in methylalco hol to hydrogenation in the presence of palladium black ashydrogenation catalyst so as to form the correspondingS-aIkoXy-I-aminoindan; and recovering the thus formedS-alkoxy-l-aminoindan.

17. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a 5-alkoXy-1-indanone dissolved in anorganic solvent therefor to hydrogenation in the presence of ahydrogenation catalyst at substantially normal pressure and slightlyincreased temperature and in the further presence of a mineral acid soas to form the corresponding S-alkoxy-l-aminoindan; and recovering thethus formed S-alkoxy-l-aminoindan.

18. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of thecrime and the oxime ether of a S-alkoxy-l-indanone dissolved in methylalcohol to hydrogenation in the presence of palladium black ashydrogenation catalyst at substantially normal pressure and at aslightly increased temperature of up to about 40 C. and in the furtherpresence of hydrochloric acid so as to form the correspondingS-alkoxy-l-aminoindan; and recovering the thus formedS-alkoxy-l-aminoindan.

19. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoxime and the oxime ether of a S-alkoxy-l-indanone, the alkoxy group ofwhich contains more than 3 carbon atoms, dissolved in methyl alcohol tohydrogenation in the presence of palladium black as hydrogenationcatalyst at substantially normal pressure and at a slightly increasedtemperature of up to about 40 C. and in the further presence ofhydrochloric acid so as to form the corresponding S-alkoxy-laminoindan;and recovering the thus formed S-alkoxy-laminoindan.

20. A method of producing a S-alkoxy-l-aminoindan, comprising the stepsof subjecting a substance selected from the group consisting of theoXime and the oxime ether of a S-alkoxy-l-indanone, the alkoxy group ofwhich contains 48 carbon atoms, dissolved in methyl alcohol tohydrogenation in the presence of palladium black as hydrogenationcatalyst at substantially normal pressure and at a slightly increasedtemperature of up to about 40 C. and in the further presence ofhydrochloric acid so as to form the corresponding S-alkoxy-l-aminoindan;and recovering the thus formed S-alkoxy-l-amihoindan.

No references cited.

1. AS A NEW COMPOSITION OF MATTER, A 1-AMINOINDAN COMPOUND HAVING THEFOLLOWING STRUCTURAL FORMULA:
 10. A METHOD OF PRODUCING A 5-ALKOXYHAN 3CARBON ATOMS, COMPRISING THE STEPS OF SUBJECTING A SUBSTANCE SELECTEDFROM THE GROUP CONSISTING OF THE OXIME AND THE OXIME ETHER OF A5-ALKOXY-1-INDANONE DISSOLVED IN AN ORGANIC SOLVENT THEREFOR TOHYDROGENATION ION THE PRESENCE OF A HYDROGENATION CATALYST SO AS TO FORMA CORRESPONDING 5ALKOXY-1-AMINO-INDAN; AND RECOVERING THE THUS FORMED5-ALKOXY-1-AMINO-INDAN.